Ligation of Endothelial α _v β ₃ Integrin Increases Capillary Hydraulic Conductivity of Rat Lung

Abstract

Complement-mediated pulmonary edema results from increases in lung capillary hydraulic conductivity (Lp), possibly by receptor-mediated mechanisms. We considered the Lp effects of vitronectin and the vitronectin-containing complement complex SC5b-9, which ligate the integrin α v β 3 . Vitronectin, SC5b-9, and SC5b-9–enriched zymosan-activated serum all rapidly increased Lp, as determined by the split-drop technique in single lung capillaries of rat lung. The Lp increases were inhibited by a monospecific (LM609) and a polyclonal (R838) antibody against the α v β 3 integrin but not by an irrelevant monoclonal antibody isotype matched with LM609, by a monoclonal antibody against the α v β 5 integrin, or by preimmune rabbit serum. Vitronectin monomers failed to increase Lp. The tyrosine kinase blockers genistein and methyl 2,5-dihydroxycinnamate caused significant concentration-dependent inhibitions of Lp increases due to vitronectin and zymosan-activated serum. By contrast, the protein kinase C blocker calphostin C had no major effect. We conclude that (1) multivalent ligation of the luminally located α v β 3 integrin of lung capillary endothelium increases transcapillary liquid flux, and (2) the dominant signal transduction pathway for this effect occurs through tyrosine kinase activation.

Barrier effects of hyperosmolar signaling in microvascular endothelium of rat lung.

“…We conclude that endothelial protein phosphorylation may be critical to the hyperosmolarity-induced increase of capillary permeability. We reported recently that ligation and aggregation of the lung endothelial ␣v␤3 integrin causes a genisteininhibitable increase of lung capillary permeability and enhancement of lung endothelial protein tyrosine phosphorylation (6,10). The similarity of the present data suggests that interventions as disparate as integrin ligation and hyperosmolarity converge on protein tyrosine phosphorylation as the common signaling pathway for endothelial barrier deterioration.…”

“…The prolonged barrier recovery to hyperosmolar exposure indicated the involvement of barrier deteriorating signal transduction mechanisms. We have shown recently that the tyrosine kinase inhibitors, genistein and MDC, block receptor-mediated increases of lung microvascular permeability (6). These inhibitors have different modes of action: genistein inhibits ATP binding to tyrosine kinase, while MDC inhibits by competing for the kinase substrate (13).…”

Pressure is proinflammatory in lung venular capillaries

“…However, as expected, the anti-αIIb antibody strongly stained platelets in whole blood. Moreover, in 4 experiments, we reconfirmed our previous finding that platelet-endothelial adhesion is not histologically evident in these isolated lungs (34). Therefore, platelets were not deposited in these capillaries.…”

“…Previously, we determined that the endothelial fluorescence of the luminal α v β 3 integrin of lung capillaries remains stable with time (34). Similarly, the immunofluorescence of another stable endothelial antigen, ACE, remained unchanged for more than 10 minutes (not shown).…”

β3-Integrin Regulates Vascular Endothelial Growth Factor-A–Dependent Permeability

“…The antagonist of ␣v␤3-integrin, LM609, has been shown to enhance vascular permeability. 51 If inhibition of ␣v␤3-integrin has the potential of elevating Flk-1 levels in endothelial cells, both angiogenesis and permeability of tumor vessels could be increased, especially if, as many are, 52 the tumor is a source of VEGF production. This might prove detrimental to the treatment of the tumor.…”